Neurotensin (NT), an endogenous peptide, exerts many actions similar to those of neuroleptic drugs. Substantial progress by our group, under support of this grant, and by other groups shows that NT modulated dopaminergic transmission in the mesolimbic system, as assessed by several neurochemical and pharmacobehavioral techniques. Interactions with dopmaine (DA) systems are of special interest because at least four important disorders of the central nervous system appear to be related to abberations of DA metabolism, schizophrenia, Parkinson's disease, Huntington's chorea and tardive dyskinesia. We now propose to study autopsy material from patients who in life suffered from one of these conditions. In addition, NT will be measured in cerebrospinal fluid (CSF) from schizophrenic patients and appropriate controls. The studies pertaining to schizophrenic tissue and CSF are intended to test the reproducibility of present findings that in such patients NT levels are elevated in frontal cortex, while in a subset of schizophrenics, NT is reduced in CSF. The neurotensin receptor binding studies in post-mortem tissue represent a novel research direction. Animal studies are designed further to explicate the exact role of NT in neurophysiological transactions. We will examine the possible mediation of NT effects by transmitters other than DA, possible actions of NT on DA autoreceptors, possible interaction of NT with the mesocortical DA system, the activity of NT in animal models of tardive dyskinesia, the possibility that chronic NT treatment may produce mesolimbic DA supersensitivity, and cognate issues. Both human and animal studies depend, in part, on the availability in our laboratory of a sensitive and specific NT radioimmunoassay, an NT receptor binding technique and HPLC technique with electrochemical detection for catecholamine assay and a variety of behavioral techniques. The long-term objective of this project is to add to our fund of knowledge regarding the pathophysiology of certain diseases of the human nervous system and thus to improve current management and treatment.